Inhibition of Aβ_16–22 Aggregation by [TEA]⁺[Ms]⁻ Follows Weakening of the Hydrophobic Core and Sequestration of Peptides in Ionic Liquid Nanodomains

We developed a coarse-grained model for the protic ionic liquid, triethylammonium mesylate ([TEA]⁺[Ms]^-), to characterize its inhibitory effects on amyloid aggregation using the K₁₆LVFFAE₂₂ fragment of the amyloid-β (Aβ_16-22) as a model amyloidogenic peptide. In agreement with previous experiments, coarse-grained molecular dynamics simulations showed that increasing concentrations of [TEA]⁺[Ms]^- in aqueous media led to increasingly small Aβ_16-22 aggregates with low beta-sheet contents. The cause of [TEA]⁺[Ms]^-'s inhibition of peptide aggregation was found to be a result of two interrelated effects. At a local scale, the enrichment of interactions between [TEA]⁺ cations and hydrophobic phenylalanine side chains weakened the hydrophobic cores of amyloid aggregates, resulting in poorly ordered structures. At a global level, peptides tended to localize at the interfaces of IL-rich nanostructures with water. At high IL concentrations, when the IL-water interface was large or fragmented, Aβ_16-22 peptides were dispersed in the simulation cell, sometimes sequestered at unaggregated monomeric states. Together, these phenomena underlie [TEA]⁺[Ms]^-'s inhibition of amyloid aggregation. This work addresses the critical lack of knowledge on the mechanisms of protein-ionic liquid interactions and may have broader implications for industrial applications.